Method for obtaining a purified hydrofluoroalkane, purified hydrofluoroalkane, use of same and method for analysing same

ABSTRACT

Process for the production of a hydrofluoroalkane, according to which hydrofluoroalkane comprising organic impurities is subjected to at least two distillations.

[0001] A subject-matter of the present invention is a process for theproduction of a purified hydrofluoroalkane, a purifiedhydrofluoroalkane, the use of the hydrofluoroalkane and a method for theanalysis of a hydrofluoroalkane.

[0002] Some hydrofluoroalkanes, such as in particular1,1,1,2-tetrafluoroethane and 1,1,1,2,3,3,3-heptafluoropropane, can beused, because of their physical properties and of their favourabletoxicology, in pharmaceutical applications, in particular as propellentgas in medical aerosols.

[0003] The industrial production of such hydrofluoroalkanes provides,however, a product which comprises saturated and unsaturated impurities.As these impurities are often toxic, strict standards are likely to beadopted, limiting the content, for example, of olefinic impurities toless than 5 ppm by volume (see, for example, the draft standard of theFDA (Food and Drug Administration, Center for Drug and Evaluation andResearch, October 1998) relating to the content of the said impuritiesin 1,1,1,2-tetrafluoroethane for MDI products).

[0004] Consequently, it is necessary to purify the hydrofluoroalkane ofindustrial grade in order to obtain a product of pharmaceutical grade.It is also necessary to have available analytical methods which make itpossible to detect and to identify traces of unsaturated and saturatedorganic impurities in the hydroflubroalkane. This presents problems, inparticular when these impurities have a boiling point close to that ofthe hydrofluoroalkane.

[0005] Patent Application WO-A-90/8750 relates to a process for thepurification of 1,1,1,2-tetrafluoroethane from olefinic impurities,according to which the 1,1,1,2-tetrafluoroethane is subjected tocatalytic hydrogenation. According to this known process, contentsranging up to 10 ppm of a single olefinic impurity, namely1,1-difluoro-2-chloroethylene, are observed. According to the patentapplication, the detection limit for 1,1-difluoro-2-chloroethylene is 10ppm. Furthermore, this known process does not make possible satisfactorypurification from all the saturated and unsaturated organic impurities.In particular, this known process does not make, it possible to remove1,1,2,2-tetrafluoroethane (HFC-134). The presence of substantial amountsof HFC-134 in 1,1,1,2-tetrafluoroethane for pharmaceutical applicationsis not desirable since its toxicity has not been examined to any extent.

[0006] It was consequently desirable to have available an efficientmanufacturing process which makes possible access to a purifiedhydrofluoroalkane, preferably of pharmaceutical grade. It wasparticularly desirable to have available a manufacturing process whichmakes possible an efficient reduction in the content of each individualorganic impurity while achieving very low overall contents of organicimpurities.

[0007] The invention consequently relates to a process for theproduction of a purified hydrofluoroalkane, according to which thehydrofluoroalkane, comprising organic impurities, is subjected to atleast two distillations, the second distillation being carried out at apressure greater than that of the first distillation, and at least onefraction composed of hydrofluoroalkane purified from organic impuritiesis recovered at the outlet of the second distillation. Generally, thisfraction can be used directly for pharmaceutical applications. However,the process according to the invention does not rule out one or moreadditional finishing stages.

[0008] The process according to the invention is particularly wellsuited to the production of a purified hydrofluoroalkane which can beused for pharmaceutical applications.

[0009] In a first alternative form of the process according to theinvention, the heavy impurities are separated from the hydrofluoroalkanein the first distillation and the light impurities are separated fromthe hydrofluoroalkane in the second distillation.

[0010] In a second alternative form of the process according to theinvention, which alternative form is preferred, the light impurities areseparated from the hydrofluoroalkane in the first distillation and theheavy impurities are separated from the hydrofluoroalkane in the seconddistillation. In this case, the fraction composed of hydrofluoroalkanepurified from organic impurities is recovered at the top of the seconddistillation.

[0011] The term “light impurity” is understood to denote an impurityexhibiting, at the pressure of the distillation, a boiling point lowerthan that of the hydrofluoroalkane. The term “heavy impurity” isunderstood to denote an impurity exhibiting, at the pressure of thedistillation, a boiling point greater than that of thehydrofluoroalkane.

[0012] It has been found, surprisingly, that the process according tothe invention makes possible an extremely efficient purification ofhydrofluoroalkane from saturated and unsaturated organic impurities,thus providing hydrofluoroalkane exhibiting a low content of the saidorganic impurities, in particular as regards its content of saturatedimpurities and, if appropriate, of (chloro)fluoroethenes and(chloro)fluoropropenes.

[0013] The process according to the invention applies to anyhydrofluoroalkane. It applies in particular to the hydrofluoroalkanescapable of being used in pharmaceutical applications. Mention may bemade, for example, of hydrofluoroethanes, hydrofluoropropanes andhydrofluorobutanes preferably exhibiting a low toxicity towards man.Specific examples of such hydrofluoroalkanes are1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoropropane,1,1,1,3,3-pentafluoropropane and 1,1,1,3,3-pentafluorobutane. Amongthese hydrofluoroalkanes, the process according to the invention appliespreferably to 1,1,1,2-tetrafluoroethane and to1,1,1,2,3,3,3-heptafluoropropane. The process according to the inventionapplies in a very particularly preferred way to the production of1,1,1,2-tetrafluoroethane of pharmaceutical grade.

[0014] The pressure in the first distillation is generally less than 10bar absolute. It is often at most 9 bar. It is preferably at most 8 bar.The pressure in the first distillation is generally at least 1 bar. Itis often at least 1.5 bar. It is preferably at least 2 bar.

[0015] The pressure in the second distillation is generally greater than10 bar absolute. It is often at least 12 bar. It is preferably at least15 bar. In a particularly preferred way, it is at least 17 bar. In avery particularly preferred way, it is at least 19 bar. The pressure inthe second distillation is generally at most 40 bar. It is often at most30 bar. It is preferably at most 25 bar.

[0016] In the present description, any reference to the pressurecorresponds to the absolute pressure measured at the top of thedistillation column.

[0017] The temperature at which the first or the second distillation iscarried out corresponds approximately to the boiling point of thehydrofluoroalkane at the pressure chosen for the respectivedistillation.

[0018] Each of the two distillations can be carried out in one or moredistillation columns. Use will preferably be made of a single column perdistillation.

[0019] The distillation columns which can be used in the processaccording to the invention are known per se. Use may be made, forexample, of conventional plate columns or plate columns of dual-flowtype or alternatively of columns with bulk or structured packing.

[0020] The number of theoretical plates in the first distillation isgenerally at least 10. It is often at least 15. A number of at least 20gives good results.

[0021] The number of theoretical plates in the second distillation isgenerally at least 20. It is often at least 30. A number of at least 40gives good results.

[0022] The molar reflux ratio in the first distillation is generally atleast 50.

[0023] The molar reflux ratio in the second distillation is generally atleast 5.

[0024] It has been found that the process according to the inventionmakes possible an extremely efficient purification of thehydrofluoroalkane from saturated and unsaturated organic impurities,thus providing hydrofluoroalkane exhibiting a low content of the saidorganic impurities, in particular as regards, if appropriate, itscontent of (chloro)fluoroethenes, of (chloro)fluoropropenes and ofsaturated impurities. This is because the process according to theinvention makes possible the production of a hydrofluoroalkane in whichthe content of each individual organic impurity has been greatlyreduced.

[0025] The invention consequently also relates to a hydrofluoroalkaneexhibiting an individual content of each organic impurity of less than10 molar ppm. This individual content is preferably at most 8 ppm. In aparticularly preferred way, this individual content is at most 5 ppm. Anindividual content of at most 2.8 ppm is very particularly preferred. Anindividual content of at most 1 ppm is even more preferred.

[0026] The contents of impurities in the hydrofluoroalkane according tothe invention can advantageously be determined according to the methoddescribed in Example 4. The hydrofluoroalkane according to the inventioncan preferably be used for pharmaceutical applications.

[0027] The total content of organic impurities in the hydrofluoroalkaneaccording to the invention is generally at most 200 molar ppm. Thistotal content is often at most 100 ppm. The total content is more oftenat most 50 ppm. The total content is preferably at most 30 ppm. In aparticularly preferred way, the total content is at most 25 ppm. A totalcontent of at most 20 ppm is even more preferred. The total content caneven be at most 5 ppm.

[0028] The total content of unsaturated organic impurities in thehydrofluoroalkane according to the invention is generally at most 5molar ppm. This content is often at most 3 ppm. The content is moreoften at most 2 ppm. The content is preferably at most 1.8 ppm. In aparticularly preferred way, the content is at most 1.7 ppm.

[0029] Hydrofluoroalkane is preferably 1,1,1,2-tetrafluoroethane.

[0030] The content of fluoropropenes determined in the1,1,1,2-tetrafluoroethane according to the invention is generally lessthan 1.4 molar ppm. This content is often at most 1.2 ppm. The contentis more often at most 1.0 ppm. The content is preferably at most 0.9ppm. In a particularly preferred way, the content is at most 0.8 ppm.

[0031] The content of 1,1,2,2-tetrafluoroethane in the1,1,1,2-tetrafluoroethane according to the invention is generally lessthan 10 molar ppm. The content is preferably at most 8 ppm. In aparticularly preferred way, the content is at most 5 ppm. In an evenmore preferred way, the content is at most 2 ppm.

[0032] The invention also relates to a method for the analysis of thecontent of organic impurities in a hydrofluoroalkane, in which method

[0033] (a) the hydrofluoroalkane is subjected to a chromatographyoperation and;

[0034] (b) an operation is carried out in which the organic impuritiesare detected by mass spectrometry.

[0035] The method according to the invention makes it possible,surprisingly, to determine, in a single analytical operation, the natureand the amount of a large number of organic impurities present in ahydrofluoroalkane. The method according to the invention even makes itpossible to carry out a quantitative detection of several organicimpurities exhibiting between them the same retention time in thechromatography operation. In a particularly surprising way, the methodaccording to the invention also makes possible the quantitativedetection of impurities which exhibit the same retention time in thechromatography operation as the hydrofluoroalkane.

[0036] It has also been found thatHCFC-124(1,1,1,2-tetrafluoro-2-chloroethane), which is an impurity whichmay be present in 1,1,1,2,3,3,3-heptafluoropropane and which could notbe determined simultaneously with other organic impurities prior to thepresent invention, can be analysed in the same operation with the otherorganic impurities by virtue of the method according to the invention.

[0037] The chromatography operation is preferably a gas chromatographyoperation.

[0038] The stationary phase in the chromatography operation is generallynonpolar. A polymer of polysiloxane type is often employed as stationaryphase. A stationary phase composed of optionally crosslinkedpolydimethylsiloxane has given good results. In the case of gaschromatography, good results have been obtained with an Rtx®-1 gaschromatography column sold by Restek Corp.

[0039] In an alternative form, the stationary phase exhibits moderatepolarity. Such a stationary phase can be composed, for example, of amixture of nonpolar polymer as described above with a polar polymer.Such polar polymers are chosen, for example, from polymersfunctionalized by polar groups, in particular from functionalizedpolyolefins or polyalkylsiloxanes. The polar group can be chosen, forexample, from hydroxyl, ether, ester, phenoxy and, preferably, fromnitrile. A polysiloxane of general formula

[0040] in which R is a C₁ to C₄ alkyl group, preferably a methyl group,is particularly preferred as polar polymer. In the alternative formdescribed above, the content of polar polymer is generally greater thanor equal to 1% by weight of the stationary phase. This content is oftengreater than or equal to 2% by weight. It is preferably greater than orequal to approximately 5% by weight. The content of polar polymer isgenerally less than or equal to 15% by weight of the stationary phase.The content is often less than or equal to 10% by weight. It ispreferably less than or equal to approximately 8% by weight.

[0041] The initial temperature of the chromatography operation isgenerally adjusted at the most to 40° C. This temperature is oftenadjusted at the most to 0° C. This temperature is more often adjusted atthe most to −20° C. This temperature is preferably adjusted at the mostto −40° C. As a general rule, it is at least −80° C.

[0042] In the chromatography operation, there is generally at least onestage with a constant temperature gradient which provides a controlledtemperature rise starting from the initial temperature. This temperaturegradient is generally at least 0.1° C./min. It is preferably at least0.5° C./min.

[0043] The temperature gradient is generally at most 10° C./min. It ispreferably at most 2° C./min.

[0044] The column is preferably a capillary column. The length of thecolumn is generally at most 200 m. The length is often at most 120 m.The length of the column is generally at least 20 m.

[0045] The injection can be carried out in split or splitless mode.Injection in split mode is preferred.

[0046] The carrier gas is often chosen from helium and hydrogen. Heliumis preferred.

[0047] The internal diameter of the column is generally at most 0.32 mm.The diameter is often at most 0.25 mm. The diameter is preferably atmost 0.20 mm. The internal diameter of the column is often at least 0.10mm. The diameter is preferably at least 0.15 mm.

[0048] The thickness of the stationary phase film deposited inside thecolumn is generally at least 0.5 μm. The thickness is preferably greaterthan or equal to approximately 1 μm. The thickness of the stationaryphase film deposited inside the column is generally at most 5 μm.

[0049] A specific alternative form of the method according to theinvention applies preferably when the internal diameter and thethickness of the film lie within the preferred ranges.

[0050] The length of the column is, in this alternative form,advantageously at least 30 m. In a more particularly preferred way, itis greater than or equal to approximately 40 m. The length of the columnis advantageously at most 100 m. In a more particularly preferred way,it is less than or equal to approximately 60 m.

[0051] In this alternative form, the temperature gradient as definedabove is generally at least 10° C./min. It is preferably at least 20°C./min. In a more particularly preferred way, the gradient is greaterthan or equal to approximately 40° C./min. The temperature gradient inthis alternative form is generally at most 50° C./min.

[0052] The initial temperature in this alternative form is generally atmost −10° C. It is preferably less than or equal to −20° C. The initialtemperature in this alternative form is generally at least −50° C.

[0053] This alternative form of the method according to the inventionmakes it possible, surprisingly, to further accelerate the analyticaloperation while retaining the other advantages of the method accordingto the invention, in particular with respect to the simultaneousdetection and determination of the organic impurities.

[0054] Premanufactured gas chromatography columns which make it possibleto implement the method according to the invention are availablecommercially, for example Rtx®-624 from Restec and DB®-624 from J & W.

[0055] Detection by mass spectrometry is preferably carried out usingthe selected ion monitoring (SIM) technique.

[0056] According to another preferred alternative form, detection bymass spectrometry is carried out using the time-of-flight (TOF)technique. Mass spectrometers for detection by using the time-of-flighttechnique, which are preferred in the method according to the invention,make it possible to record a high number of mass spectra per second,namely approximately 1 to 500, preferably 100 to 500, spectra persecond. Spectrometers which can be used for the implementation of themethod according to the invention are, for example, those sold by LecoCorporation under the name Pegasus® II and those sold by Thermoquestunder the name Tempus™.

[0057] The hydrofluoroalkanes for which the content of organicimpurities can be analysed by the method according to the invention arethe same as those obtained according to the process according to theinvention. The method according to the invention applies, preferably, tothe analysis of 1,1,1,2-tetrafluoroethane or of1,1,1,2,3,3,3-heptafluoropropane. It applies in particular to theanalysis of 1,1,1,2-tetrafluoroethane.

[0058] The method according to the invention is particularly efficientas determination of the content of all the organic impurities can beobtained by a single analytical operation. That being the case, onlythis operation has to be validated, that is to say standardized andconfirmed. Consequently, the calibration possibly needed between theanalysis of various samples is simplified.

[0059] The method according to the invention makes it possible toachieve a very short duration necessary for the analysis, which cantypically be carried out in less than two hours, often in less than onehour. A complete analysis of the impurities can be arrived at in a timeof approximately 10 minutes. This efficiency makes it possible inparticular to improve the performance of industrial manufacturingprocesses requiring control of the quality of a hydrofluoroalkane. Thisis because it is possible to meet, with greater flexibility and speed,urgent orders for hydrofluoroalkane and reduce the hydrofluoroalkanestorage times.

[0060] The invention consequently also relates to a process for themanufacture of a hydrofluoroalkane comprising the use of the analyticalmethod according to the invention for controlling the quality of thehydrofluoroalkane.

[0061] In an alternative form, the hydrofluoroalkane is a purifiedhydrofluoroalkane. In this alternative form, the process for themanufacture of a hydrofluoroalkane often comprises a purification stage.This process preferably comprises

[0062] (a) the use of the method according to the invention for theanalysis of a crude hydrofluoroalkane;

[0063] (b) a purification of the crude hydrofluoroalkane in order toobtain a purified hydrofluoroalkane;

[0064] (c) and a second use of the method according to the invention forthe analysis of the purified hydrofluoroalkane.

[0065] If appropriate, the purification can be carried out, for example,according to the production process according to the invention. Theprocess for manufacturing a hydrofluoroalkane according to the inventionpreferably applies to the hydrofluoroalkanes mentioned above.

[0066] The invention also relates to a process for the manufacture of apharmaceutical aerosol, comprising at least one hydrofluoroalkane ofpharmaceutical grade, comprising the use of the analytical methodaccording to the invention for controlling the quality of thehydrofluoroalkane of pharmaceutical grade.

[0067] The process for the manufacture of a pharmaceutical aerosolaccording to the invention is particularly suitable for the manufactureof a pharmaceutical aerosol for inhalation comprising at least onehydrofluoroalkane liquefied under pressure and a medicament. Themedicament is preferably present in the form of a powder in thesuspended state. The hydrofluoroalkane is present as propellent gas.

[0068] The process for the manufacture of a pharmaceutical aerosol isparticularly advantageous as the analytical method makes it possible tocarry out, in a particularly efficient way, the strict quality controllaid down for pharmaceutical applications.

[0069] The invention also relates to the use of the hydrofluoroalkaneaccording to the invention as propellent gas in pharmaceutical aerosols.

[0070] The invention also relates to the use of the hydrofluoroalkaneaccording to the invention in the electronics industry.

[0071]FIG. 1 represents a diagram of a plant which can be used forimplementing the preferred alternative form of the production processaccording to the invention. The numbers refer to FIG. 1. Thehydrofluoroalkane comprising organic impurities is introduced via route(1) into a first distillation column (2). At the top (3) of this column(2), a fraction is obtained comprising light impurities (lower butsimilar boiling point) and those which form a minimum-boiling azeotropeat this pressure. At the bottom (4) of this column (2), a fraction isobtained comprising hydrofluoroalkane with a reduced content of otherimpurities, which fraction is introduced via route (5) into the seconddistillation column (6) operating at a higher pressure than the column(2). At the bottom (7) of the second column (6), a fraction is recoveredwhich is enriched in heavy impurities which exhibit a higher boilingpoint with respect to that of the hydrofluoroalkane. At the top (8) ofthe second column (6), hydrofluoroalkane is obtained which is purifiedfrom organic impurities.

[0072] The examples given below are intended to illustrate, withoutimplied limitation, the process, the analytical method and ahydrofluoroalkane according to the invention.

EXAMPLE 1

[0073] (In Accordance with the Invention)

[0074] An impure 1,1,1,2-tetrafluoroethane fraction comprising 57.2molar ppm of saturated organic impurities and 10.6 molar ppm ofunsaturated organic impurities was employed. This fraction wasintroduced at the level of the 7th theoretical plate into a firstdistillation column comprising 20 theoretical plates. The pressure inthe first column was 6.75 bar abs. A reflux ratio of 250 was provided. Afraction was withdrawn at the top corresponding to 10% of the feed andcomprising 51.4 molar ppm of saturated organic impurities and 3.9 molarppm of unsaturated organic impurities. A fraction was recovered at thebottom composed of 1,1,1,2-tetrafluoroethane and purified from “light”impurities comprising 41.5 molar ppm of saturated organic impurities and34.9 molar ppm of unsaturated organic impurities, which fraction wasintroduced at the level of the 13th plate into a second distillationcolumn comprising 20 theoretical plates. The pressure in this seconddistillation column was 19.3 bar absolute. A reflux ratio of 14.8 wasprovided. At the column bottom, 10% of the feed of the first column,comprising 320 molar ppm of saturated organic impurities and 9.8 molarppm of unsaturated organic impurities was withdrawn. A fraction waswithdrawn at the top of this column composed of1,1,1,2-tetrafluoroethane purified from heavy impurities comprising 10.7molar ppm of saturated organic impurities and 1.3 molar ppm ofunsaturated organic impurities.

EXAMPLE 2

[0075] (Not in Accordance with the Invention)

[0076] An impure 1,1,1,2-tetrafluoroethane fraction comprising 2 750molar ppm of saturated organic impurities and 75 molar ppm ofunsaturated organic impurities was employed. This fraction wasintroduced at the level of the 14th theoretical plate into a firstdistillation column comprising 20 theoretical plates. The pressure inthe first column was 13 bar abs. A reflux ratio of 50 was provided. Afraction was withdrawn at the top corresponding to 10% of the feed andcomprising 1 950 molar ppm of saturated organic impurities and 150 molarppm of unsaturated organic impurities. A fraction was recovered at thebottom composed of 1,1,1,2-tetrafluoroethane purified from “light”impurities comprising 2 950 molar ppm of saturated organic impuritiesand 40 ppm of unsaturated organic impurities, which fraction wasintroduced at the level of the 14th plate into a second distillationcolumn comprising 20 theoretical plates. The pressure in this seconddistillation column was 12 bar absolute. A reflux ratio of 12.5 wasprovided. At the column bottom, 10% of the feed of the first column,comprising 15 500 molar ppm of saturated organic impurities and 50 molarppm of unsaturated organic impurities, was withdrawn. A fraction waswithdrawn at the top of this column composed of1,1,1,2-tetrafluoroethane purified from heavy impurities comprising 275molar ppm of saturated organic impurities and 31 molar ppm ofunsaturated organic impurities.

EXAMPLE 3

[0077] (Not in Accordance with the Invention)

[0078] An impure 1,1,1,2-tetrafluoroethane fraction, comprising 2 950molar ppm of saturated organic impurities and 50 molar ppm ofunsaturated organic impurities, was employed. This factor was introducedat the level of the 14th theoretical plate into a first distillationcolumn comprising 20 theoretical plates. The pressure in the firstcolumn was 7.5 bar abs. A reflux ratio of 50 was provided. A fractionwas withdrawn at the top corresponding to 10% of the feed and comprising1 830 molar ppm of saturated organic impurities and 200 molar ppm ofunsaturated organic impurities. A fraction was recovered at the bottomcomposed of 1,1,1,2-tetrafluoroethane purified from “light” impuritiescomprising 3 200 molar ppm of saturated organic impurities and 32 ppm ofunsaturated organic impurities, which fraction was introduced at thelevel of the 14th plate into a second distillation column comprising 20theoretical plates. The pressure in this second distillation column was6.5 bar absolute. A reflux ratio of 12.5 was provided. At the columnbottom, 10% of the feed of the first, column, comprising 27 500 molarppm of saturated organic impurities and 50 molar ppm of unsaturatedorganic impurities, was withdrawn. At the top of this column, a fractionwas withdrawn composed of 1,1,1,2-tetrafluoroethane purified from heavyimpurities comprising 200 molar ppm of saturated organic impurities and28 molar ppm of unsaturated organic impurities.

EXAMPLE 4

[0079] An analysis of 1,1,1,2-tetrafluoroethane of pharmaceutical gradeobtained according to a production process in accordance with theinvention was carried out. To do this, gas chromatography was carriedout on an Rtx®-1 gas chromatography column sold by Restek Corp.comprising, as stationary phase, 100% of dimethylpolysiloxanecrosslinked by the Crossbond® process. The dimensions of the column were105 m×0.25 mm×1.0 micron. A temperature programme comprising 2 stageswas used, the first beginning at −50° C., and the temperature was raisedat a rate of 1° C./min to a temperature of 0° C. Subsequently, in asecond stage, the temperature was raised at a rate of 10° C./min to 250°C. Detection was carried out by mass spectrometry with the selected ionmonitoring (SIM) technique using an HP 5972 mass spectrometer sold byHewlett-Packard. Standardization was carried out by employing a gasstandard mixture composed of 10 ppm of each impurity to be analysed.

[0080] The contents of various impurities in the1,1,1,2-tetrafluoroethane according to the invention and in the crude1,1,1,2-tetrafluoroethane which is employed in the process according tothe invention are shown in the table below. The detection limit of theanalytical method according to the invention is also shown. Thisdetection limit was validated by random calibration with respect to 5concentrations of 1 to 10 ppm of each individual impurity. The valuesobtained were corrected according to the purity of each of theimpurities present in the calibration mixture.

[0081] The table also includes the values contained in the draft FDAstandard mentioned above. All the values are expressed in molar ppm,apart from the “Assay” value, which is expressed as a percent. An emptybox means that the impurity in question was not observed. Detectionlimit of the method Draft Crude HFC- Organic according to FDA HFC- 134Aimpurity Formula the invention standard 134a Invention HFC-23 CHF₃ 0.2 5CFC-13 CClF₃ 0.3 5 < HFC-32 CH₂F₂ 0.2 5 HFC-125 CHF₂—CF₃ 0.3 5 50HFC-143a CH₃—CF₃ 0.4 10 124 CFC-115 CClF₂—CF₃ 0.2 5 0.3 HFC-1123 CHF═CF₂0.2 5 c/t-HFC- CF₃—CF═CF—CF₃ 0.7 5 1318my t/c-HFC- CF₃—CF═CF—CF₃ 0.3 5 << 1318my (1) HFC-245cb CF₃—CF₂—CH₃ 0.2 5 0.3 HFC-1234yf CH₂═CF—CF₃ 0.3 51.3 HFC-134 CHF₂—CHF₂ 0.4 1 000 2 824 < HFC-152a CH₃—CHF₂ 0.2 300 1.3HFC-217ba CF₃—CCIF—CF₃ 0.5 5* 2.4 0.5 HFC-161 CH₃—CH₂F 0.2 30 HFC-1225yeCHF═CF—CF₃ 0.2 5 1.8 HFC-1243zf CH₂═CH—CF₃ 0.4 5 7.3 0.9 HFC-1132CHF═CHF 0.4 5 < C₃H₂F₄ (2) 0.3 5* 11.8 HCFC-22 CHClF₂ 0.2 50 0.2 HFC-CF₃—CH═CH—CF₃ 0.5 5 1336mzz CFC-12 CCl₂F₂ 0.2 100 0.2 HCC-40 CH₃Cl 0.4 54.0 HCFC-124a CHF₂—CClF₂ 0.2 5 HCFC-124 CHClF—CF₃ 0.4 100 36 HCFC-1122CHCl═CF₂ 0.3 5 28 0.3 HCFC-31 CH₂ClF 0.4 5 0.4 CFC-114 CClF₂—CClF₂ 0.1 5CFC-114a CCl₂F—CF₃ 0.1 25 19 HFC-152 CH₂F—CH₂F 0.5 5 c/t-HCFC- CHF═CClF0.3 5* 4.6 1122a (3) c/t-HCFC- CHF═CClF 0.3 5* < 1122a (3) HCFC-133aCH₂Cl—CF₃ 0.4 5 0.4 trans- CHCl═CHF 0.5 5* 10.3 0.2 HCFC-1131 cis-HCFC-CHCl═CHF 0.5 5* 1131 CFC-12B1 CClBrF₂ 0.2 5 CFC-1112a CF₂═CCl₂ 0.3 5HCFC-123 CHCl₂—CF₃ 0.4 5 CFC-11 CCl₃F 0.3 5 HCFC-123a CHClF—CClF₂ 0.3 5c/t-HCFC- CHCl═CClF 0.2 5 1121 HCC-30 CH₂Cl₂ 0.6 5* < HCFC-132bCClF₂—CH₂Cl 0.6 5 CFC-113 CClF₂—CCl₂F 0.4 5 HCC-1120 CHCl═CCl₂ 0.8 5* << Sum of 1 000 3 127.6 1.9 organic impurities Sum of 5 65.1 1.4 olefinsAssay 99.9% 100%  

[0082] It is apparent that the 1,1,2,2-tetrafluoroethane according tothe invention, obtained in accordance with the process according to theinvention, exhibits a content of organic impurities which is extremelylow and far below the values of the draft FDA standard. Furthermore, noindividual organic impurity has a content exceeding 1 molar ppm.

[0083] It is also apparent that the method according to the inventionmakes it possible to detect and to identify, with an extremely highsensitivity, all the impurities included in the draft FDA standard.

1. Process for the production of purified 1,1,1,2-tetrafluoroethane,according to which 1,1,1,2-tetrafluoroethane, comprising organicimpurities, is subjected to at least two distillations, the seconddistillation being carried out at a pressure greater than that of thefirst distillation, and at least one fraction composed ofhydrofluoroalkane purified from organic impurities is recovered at theoutlet of the second distillation.
 2. Process according to claim 1, inwhich the pressure in the first distillation is less than 10 bar and thepressure in the second distillation is at least 10 bar.
 3. Processaccording to claim 1 or 2, in which the pressure in the firstdistillation is at most 9 bar.
 4. Process according to claim 3, in whichthe pressure in the first distillation is at most 8 bar.
 5. Processaccording to any one of claims 1 to 4, in which the pressure in thesecond distillation is at least 15 bar.
 6. Process according to claim 5,in which the pressure in the second distillation is at least 19 bar. 7.Process according to any one of claims 1 to 6, in which the fractioncomposed of 1,1,1,2-tetrafluoroethane purified from organic impuritiesis recovered at the top of the second distillation.
 8. Purified1,1,1,2-tetrafluoroethane, exhibiting an individual content of eachorganic impurity of less than 10 molar ppm.
 9. 1,1,1,2-Tetrafluoroethaneaccording to claim 8, exhibiting an individual content of each organicimpurity of at most 5 molar ppm.
 10. 1,1,1,2-Tetrafluoroethane accordingto claim 8 or 9, additionally exhibiting a total content of organicimpurities of at most 200 molar ppm.
 11. Use of the1,1,1,2-tetrafluoroethane according to any one of claims 8 to 10 aspropellent gas in pharmaceutical aerosols.
 12. Method for the analysisof the content of organic impurities in a hydrofluoroalkane, in which(a) the hydrofluoroalkane is subjected to a chromatography operationand; (b) an operation is carried out in which the organic impurities aredetected by mass spectrometry.
 13. Method according to claim 12, inwhich the chromatography operation is a gas chromatography operation.14. Method according to claim 12 or 13, in which the initial temperatureof the chromatography operation is adjusted at the most to 40° C. 15.Method according to claim 14, in which the initial temperature of thechromatography operation is less than or equal to approximately −20° C.16. Method according to any one of claims 12 to 15, in which detectionis carried out using the selected ion monitoring (SIM) technique. 17.Method according to any one of claims 12 to 15, in which detection iscarried out using the time-of-flight (TOF) technique.
 18. Methodaccording to any one of claims 12 to 17, in which the hydrofluoroalkaneis chosen from 1,1,1,2,3,3,3-heptafluoropropane,1,1,1,3,3-pentafluoropropane, 1,1,1,3,3-pentafluorobutane and1,1,1,2-tetrafluoroethane.
 19. Method according to claim 18, in whichthe hydrofluoroalkane is 1,1,1,2-tetrafluoroethane.
 20. Process for themanufacture of a hydrofluoroalkane comprising the use of the methodaccording to any one of claims 12 to 19 for controlling the quality ofthe hydrofluoroalkane.
 21. Process for the manufacture of apharmaceutical aerosol, comprising at least one hydrofluoroalkane ofpharmaceutical grade, comprising the use of the method according to anyone of claims 12 to 19 for controlling the quality of thehydrofluoroalkane of pharmaceutical grade.
 22. Process for theproduction of a purified hydrofluoroalkane chosen from1,1,1,2,3,3,3-heptafluoropropane, 1,1,1,3,3-pentafluorouropane and1,1,1,3,3-pentafluorobutane, according to which the hydrofluoroalkane,comprising organic impurities, is subjected to at least twodistillations, the second distillation being carried out at a pressuregreater than that of the first distillation, and at least one fractioncomposed of hydrofluoroalkane purified from organic impurities isrecovered at the outlet of the second distillation.
 23. Processaccording to claim 22, in which the fraction composed ofhydrofluoroalkane purified from organic impurities is recovered at thetop of the second distillation.
 24. Purified hydrofluoroalkane,exhibiting an individual content of each organic impurity of less than10 molar ppm.